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Methamphetamine is a highly addictive stimulant known to cause neurotoxicity, cognitive deficits, and immune dysregulation in the brain. Despite significant research, the molecular mechanisms driving methamphetamine-induced neurotoxicity and glial cell dysfunction remain poorly understood. This study investigates how methamphetamine disrupts glial cell function and contributes to neurodevelopmental and neurodegenerative processes. Using single-cell RNA sequencing (scRNA-seq), we analyzed the transcriptomes of 4000 glial cell-associated genes from the cortical regions of mice chronically administered methamphetamine. Methamphetamine exposure altered the key pathways in astrocytes, including the circadian rhythm and cAMP signaling; in microglia, affecting autophagy, ubiquitin-mediated proteolysis, and mitophagy; and in oligodendrocytes, disrupting lysosomal function, cytoskeletal regulation, and protein processing. Notably, several transcription factors, such as Zbtb16, Hif3a, Foxo1, and Klf9, were significantly dysregulated in the glial cells. These findings reveal profound methamphetamine-induced changes in the glial transcriptomes, particularly in the cortical regions, highlighting potential molecular pathways and transcription factors as targets for therapeutic intervention. This study provides novel insights into the glial-mediated mechanisms of methamphetamine toxicity, contributing to our understanding of its effects on the central nervous system and laying the groundwork for future strategies to mitigate its neurotoxic consequences. [ABSTRACT FROM AUTHOR]

As per the National Survey on Drug Use and Health, 10.5% of Americans aged 12 years and older are suffering from alcohol use disorder, with a wide range of neurological disorders. Alcohol-mediated neurological disorders can be linked to Alzheimer's-like pathology, which has not been well studied. We hypothesize that alcohol exposure can induce astrocytic amyloidosis, which can be corroborated by the neurological disorders observed in alcohol use disorder. In this study, we demonstrated that the exposure of astrocytes to ethanol resulted in an increase in Alzheimer's disease markers—the amyloid precursor protein, Aβ1-42, and the β-site-cleaving enzyme; an oxidative stress marker—4HNE; proinflammatory cytokines—TNF-α, IL1β, and IL6; lncRNA BACE1-AS; and alcohol-metabolizing enzymes—alcohol dehydrogenase, aldehyde dehydrogenase-2, and cytochrome P450 2E1. A gene-silencing approach confirmed the regulatory role of lncRNA BACE1-AS in amyloid generation, alcohol metabolism, and neuroinflammation. This report is the first to suggest the involvement of lncRNA BACE1-AS in alcohol-induced astrocytic amyloid generation and alcohol metabolism. These findings will aid in developing therapies targeting astrocyte-mediated neurological disorders and cognitive deficits in alcohol users. [ABSTRACT FROM AUTHOR]

NeuroHIV affects approximately 30–60% of people living with HIV-1 (PLWH) and is characterized by varying degrees of cognitive impairments, presenting a multifaceted challenge, the underlying cause of which is chronic, low-level neuroinflammation. Such smoldering neuroinflammation is likely an outcome of lifelong reliance on antiretrovirals coupled with residual virus replication in the brains of PLWH. Despite advancements in antiretroviral therapeutics, our understanding of the molecular mechanism(s) driving inflammatory processes in the brain remains limited. Recent times have seen the emergence of non-coding RNAs (ncRNAs) as critical regulators of gene expression, underlying the neuroinflammatory processes in HIV infection, NeuroHIV, and their associated comorbidities. This review explores the role of various classes of ncRNAs and their regulatory functions implicated in HIV infection, neuropathogenesis, and related conditions. The dysregulated expression of ncRNAs is known to exacerbate the neuroinflammatory responses, thus contributing to neurocognitive impairments in PLWH. This review also discusses the diagnostic and therapeutic potential of ncRNAs in HIV infection and its comorbidities, suggesting their utility as non-invasive biomarkers and targets for modulating neuroinflammatory pathways. Understanding these regulatory roles could pave the way for novel diagnostic strategies and therapeutic interventions in the context of HIV and its comorbidities. [ABSTRACT FROM AUTHOR]

Antiretroviral treatments have notably extended the lives of individuals with HIV and reduced the occurrence of comorbidities, including ocular manifestations. The involvement of endoplasmic reticulum (ER) stress in HIV-1 pathogenesis raises questions about its correlation with cellular senescence or its role in initiating senescent traits. This study investigated how ER stress and dysregulated autophagy impact cellular senescence triggered by HIV-1 Tat in the MIO-M1 cell line (human Müller glial cells). Cells exposed to HIV-1 Tat exhibited increased vimentin expression combined with markers of ER stress (BiP, p-eIF2α), autophagy (LC3, Beclin-1, p62), and the senescence marker p21 compared to control cells. Western blotting and staining techniques like SA-β-gal were employed to examine these markers. Additionally, treatments with ER stress inhibitor 4-PBA before HIV-1 Tat exposure led to a decreased expression of ER stress, senescence, and autophagy markers. Conversely, pre-treatment with the autophagy inhibitor 3-MA resulted in reduced autophagy and senescence markers but did not alter ER stress markers compared to control cells. The findings suggest a link between ER stress, dysregulated autophagy, and the initiation of a senescence phenotype in MIO-M1 cells induced by HIV-1 Tat exposure. [ABSTRACT FROM AUTHOR]

Our previous findings demonstrated that astrocytic HIF‐1α plays a major role in HIV‐1 Tat‐mediated amyloidosis which can lead to Alzheimer's‐like pathology‐a comorbidity of HIV‐Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV‐1 Tat stimulated astrocyte‐derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF‐1α could likely mitigate HIV‐1 Tat‐ADEV‐mediated neuronal injury. Rat hippocampal neurons when exposed to HIV‐1 Tat‐ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF‐1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV‐1 Tat‐ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV‐1 Tat‐ADEVs, exhibited behavioural changes, and Alzheimer's 's‐like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF‐1α silenced ADEVs. This is the first report demonstrating the role of amyloid‐carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF‐1α. [ABSTRACT FROM AUTHOR]

IntroductionAlthough cART has dramatically improved the life span of persons living with HIV (PLWH) and transformed the infection to more or less a medically manageable chronic disease (1), the incidence [...], In the era of combined antiretroviral therapy (cART), lung diseases such as chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD) are common among persons living with HIV (PLWH), particularly smokers. Although smoking is highly prevalent among PLWH, HIV may be an independent risk factor for lung diseases; however, the role of HIV and cigarette smoke (CS) and their potential interaction in the development of chronic lung diseases among PLWH has not been delineated. To investigate this interaction, cynomolgus macaques were exposed to CS and/or simian-adapted human immunodeficiency virus (SHIV) and treated with cART. The development of CB and the lung functions were evaluated following CS [+ or -] SHIV treatment. The results showed that in the lung, SHIV was a strong independent risk factor for goblet cell metaplasia/hyperplasia and mucus formation, MUC5AC synthesis, loss of tight junction proteins, and increased expression of Th2 cytokines/transcription factors. In addition, SHIV and CS synergistically reduced lung function and increased extrathoracic tracheal ring thickness. Interestingly, SHIV infection generated significant numbers of [HIV-gp120.sup.+] epithelial cells (HGECs) in small airways and alveoli, and their numbers doubled in CS+SHIV-infected lungs. We conclude that even with cART, SHIV independently induces CB and pro-COPD changes in the lung, and the effects are exacerbated by CS.